This project is designed to assess the clinical and brain metabolic progression of age-related mental decline in the autos dominant form of familial Alzheimer disease (FAD). Families with autosomal dominant inheritance patterns for AD are rare, but such pedigrees provide information for linkage analysis of the FAD gene(s). Longitudinal investigation of "at-risk" relatives in these pedigrees is an efficient approach for studying early diagnosis and disease course because 50% of relatives eventually develop the disease. Our group already has recruited 21 FAD pedigrees, with 410 living relatives (41 demented, 175 at-risk, and 194 others) potentially available for study. We propose to perform annual clinical and neuropsychological assessments on 58 relatives at risk for FAD. Positron emission tomography (PET) scans, using [F.18] fluorodeoxyglucose (FDG), and magnetic resonance imaging (MRI) scans will be performed at baseline and follow-up year 4. Twenty-eight controls will have baseline and follow-up (year 4) imaging and neuropsychological studies. PET data will be registered with MRI data, and quantitative volumetric MRI analyses will be used to explore relationships of brain structures to clinical and metabolic decline. It is hypothesized that initial cerebral metabolic patterns (determined with PET) will predict clinical and metabolic decline. We also expect relatives from families with early-onset dementia (< 65 years) to show more severe mental decline than those from late-onset families. Our prior studies demonstrated parietal hypometabolism in patients with mild dementias who later developed probable sporadic (i.e., nonfamilial) AD, with more profound hypometabolism found in early-onset patients. The proposed project aims to replicate such findings in relatives at risk for FAD. Blood will be drawn for DNA analyses of candidate genes for linkage studies. We predict that PET data will improve accuracy of clinical diagnoses early in the disease course, thus defining neurobiologically homogeneous FAD pedigrees and improving accuracy of genetic linkage analyses. Associations with relevant markers also will be explored in familial subgroups defined according to age at dementia onset and cerebral metabolic pattern. The goals of the proposed study parallel our successful ongoing studies of Huntington disease. We will identify presymptomatic putative FAD gene carriers, determine the time course for cerebral metabolic progression of the disease, identify homogeneous subject groups most likely to benefit from experimental therapies, and provide an objective, noninvasive means to metabolically monitor experimental therapeutic trials.